In the periphery system, serotonin exhibits effects of smooth muscle relaxation, platelet aggregation, and gastrointestinal tract function regulation. On the other hand, in the central nervous system, serotonin functions as a neurotransmitter and is deeply associated with the motor system, perceptive system, physiological functions such as body temperature regulation, sleep, feeding behavior, vomiting, sexual behavior, neuroendocrine system, cognition and memory, or biorhythm, and pathologic conditions such as anxiety, aggression, obsession, mood disorder, hallucination, schizophrenia, autism, or drug dependence (refer to Non-Patent Document 1, Non-Patent Document 2, for example).
Serotonin receptor is classified into 7 families ranging from 5-HT1 to 5-HT7. 5HT1 is composed of 5 subtypes (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F).
5-HT1A receptor is widely distributed in the central nervous system. In the brain, this receptor is distributed at a high density, particularly in the cerebral limbic system, mainly in the hippocampus, the septum, the amygdaloid complex, and the nuclei raphes. In the spinal cord, it is distributed at a high density in the posterior horn cortex which primary afferent fibers project (I and II laminae), the anterior horn inner portion where motoneurons are localized (VIII-IX laminae), and the intermediolateral nucleus where preganglionic sympathetic cells are present (VII lamina). In the nerve, a serotonin receptor exists as a presynaptic receptor in the cell bodies of the serotonin nerve (5-HT1A somatodendritic autoreceptor), and as a postsynaptic receptor, exists on the nerve in which the serotonin nerve innervates. Such a presynaptic receptor conducts negative feedback regulation to serotonin release.
The action of a 5-HT1A receptor in a living body and diseases in which the receptor is involved have been clarified as a result of the discovery of agonists and antagonists that are selective for the 5-HT1A receptor.
Depression and anxiety disorder are examples of such diseases. It is considered that a presynaptic 5-HT1A receptor is important for treating depression. It is considered that a selective serotonin reuptake inhibitor (SSRI) and a selective serotonin/noradrenalin reuptake inhibitor (SNRI) that are currently used as therapeutic agents. These agents inhibit the uptake of these transmitters in nerve cells, so as to increase the concentration of the transmitters in a synaptic cleft, and that as a result, desensitizes a receptor, thereby exhibiting efficacy. Recently, it has been reported that (−) pindolol (which exhibits affinity for adrenaline β and 5-HT1A receptor and has an antagonistic effect against 5-HT1A receptor) promotes the onset of the pharmacological effects of SSRI, thereby increasing the effective rate thereof in patients with depression. This may be because the release of serotonin at the nerve terminals is increased by the blockage of a presynaptic 5-HT1A receptor, so that the desensitization of the receptor is advanced (refer to Non-Patent Document 3, for example).
The study of Barros M. et al. using marmosets is a report suggesting a possibility of the use of a 5-HT1A receptor antagonist for anxiety disorder. Using, as an index, the fear and anxiety behavior of a marmoset provoked by showing the stuffed specimen of a predaceous animal to the marmoset, the effect of a 5-HT1A receptor antagonist on anxiety was studied. As a result, it was shown that this agent has an anxiolytic effect (refer to Non-Patent Document 4, for example). These results suggested a possibility that the 5-HT1A receptor antagonist is useful as an agent for preventing or treating depression or anxiety disorder.
It has also been strongly suggested that the 5-HT1A receptor is associated with cognition, memory, and learning. An NMDA-type glutamate receptor antagonist, or the fornix transection induce cognitive disorder. Such cognitive disorder was improved by a 5-HT1A receptor antagonist (refer to Non-Patent Document 5 and Non-Patent Document 6, for example). Yasuno F. et al. administered a 5-HT1A receptor antagonist labeled with 11C ([11C]WAY-100635) to a human. Thereafter, they examined the relationship between memory and a portion shared by the 5-HT1A receptor by positron emission tomography (refer to Non-Patent Document 7, for example). As a result, a negative correlation was found between the improvement of remembrance and the affinity of [11C]WAY-100635 to bind to a hippocampal postsynaptic 5-HT1A receptor. This result suggests that postsynaptic 5-HT1A receptors distributed over the hippocampus have a negative effect on the memory. These findings suggest a possibility that a 5-HT1A receptor antagonist is effective for cognitive disorder, or memory or learning disorder.
Also, in recent years, the association of a 5-HT1A receptor with urinary reflex has been reported (refer to Non-Patent Document 8, for example).
Various subjective symptoms provoked by urinary dysfunction are generically called lower urinary tract symptoms. Such lower urinary tract symptoms are broadly divided into symptoms regarding urinary storage such as increased urinary frequency, urinary urgency, or urinary incontinence, and voiding symptoms such as difficulty of urination or anuresis. Urinary incontinence is further classified into stress incontinence, urge incontinence, overflow incontinence, reflex urinary incontinence, extraurthral incontinence, or the like. Urinary incontinence having both the symptom of stress incontinence and that of urge incontinence is called mixed urinary incontinence. In the International Continence Society (ICS) that took place in 2001, the following proposal was given: “The overactive bladder is a medical condition referring to the symptoms of frequency and urgency, with or without urge incontinence, when appearing in the absence of local pathologic or metabolic factors that would account for these symptoms.” Thus, a pathologic condition determined mainly based on subjective symptoms was defined as overactive bladder.
Examples of a cause of symptoms regarding urine pooling storage may include neuropathic bladder caused by encephalopathy (including cerebrovascular disorder, Parkinson's disease, brain tumor, multiple sclerosis, and the like), senile dementia, myelopathy, or spinal disease, unstable bladder, benign prostatic hyperplasia, prostatic cancer, bladder neurosis, interstitial bladder cystitis, bladder irritation caused by chronic cystitis or chronic prostatitis, cytoplasm, enuresis (including nocturnal enuresis), Nectria, and psychogenic dysuria.
In studies regarding urinary reflex in rats, a 5-HT1A receptor agonist promotes urinary reflex (refer to Non-Patent Document 8, for example), whereas a 5-HT1A receptor antagonist suppresses urinary reflex measured by rhythmical bladder contraction or cystometogram. In addition, in the case of a 5-HT1A receptor partial agonist, the effect to suppress urinary reflex is reduced depending on the degree of the agonistic action of the agent (refer to Non-Patent Document 9, for example). From these findings, a 5-HT1A receptor antagonist is anticipated as a novel agent for treating symptoms regarding urinary storage based on a novel action mechanism (including increased urinary frequency, urinary urgency, and urinary incontinence, etc.) (refer to Non-Patent Document 10, for example).
Other than the aforementioned diseases, there is a wide range of diseases in which a 5-HT1A receptor would be involved. Examples of such a disease may include neuropsychiatic disorder (e.g. obsessive-compulsive disorder (refer to Non-Patent Document 11, for example), borderline personality disorder (refer to Non-Patent Document 12, for example), post-traumatic stress disorder (refer to Non-Patent Document 13, for example), panic disorder, schizophrenia (refer to Non-Patent Document 14, for example), genital insufficiency (refer to Non-Patent Document 14, for example), alcohol and/or cocaine dependence (refer to Non-Patent Document 15 and Non-Patent Document 16, for example), sleep disorder (refer to Non-Patent Document 14, for example), pain (refer to Non-Patent Document 14, for example), migraine (refer to Non-Patent Document 17, for example), visual attention disorder (refer to Non-Patent Document 18, for example), temperature instability (refer to Non-Patent Document 14, for example), vomiting (refer to Non-Patent Document 19, for example), gastrointestinal disorder (refer to Non-Patent Document 14, for example), eating disorder (refer to Non-Patent Document 14, for example), hypertension (refer to Non-Patent Document 20, for example), neuro-degenerative disease (refer to Non-Patent Document 21 and Non-Patent Document 22, for example) (e.g. cerebral ischemia, Alzheimer's disease, etc.), dyskinesia caused by Parkinson's disease (refer to Non-Patent Document 23, for example), and symptoms associated with withdrawal from nicotine ingestion or smoking (refer to Non-Patent Document 24, for example).
Accordingly, a 5-HT1A receptor antagonist is expected as an agent for preventing or treating such a wide range of diseases. Although studies for developing such a 5-HT1A receptor antagonist have actively been conducted, the agent has not yet been on the market. Thus, the development of a superior 5-HT1A receptor antagonist has been desired.
A large number of reports have previously been made regarding compounds having an antagonistic effect against a 5-HT1A receptor. However, for the use as an agent for treating lower urinary tract symptoms, only a few compounds described in Patent Document 1 and Patent Document 2 have been known.
The compound described in Patent Document 1 is a compound represented by the following formula or a pharmacologically acceptable salt thereof:
wherein R represents a hydrogen atom or the like; R1 represents a hydrogen atom or the like; R2 represents a halogen atom or the like; and B represents a monocyclic aryl group or the like. The structural characteristics of this compound are that it has an N-phenylaminoalkyl group as a piperazine side chain.
Accordingly, in terms of chemical structure, the compound described in Patent Document 1 completely differs from the compound represented by formula (I) of the present invention characterized in that “it has an unsubstituted or monosubstituted carbamoyl group at position 6 on an indole skeleton, and has a methoxy group on an aryl group of an aryl alkyl side chain extended from a nitrogen atom on a piperidine ring, at an ortho position to the alkyl side chain.”
Patent Document 2 is a prior art that is closest to the present invention. This document discloses an agent for treating lower urinary tract symptoms containing a compound represented by the following formula, a salt thereof, or a hydrate thereof:
wherein the Ar1 ring represents a benzene ring or the like; D represents a nitrogen atom or the like; R3 and R4 identically or differently represent hydrogen atoms or the like; R5 represents a hydrogen atom or the like; R1 and R2 represent hydrogen atoms or the like, or bind to each other, so as to form a ring containing X; and m represents 0 or an integer between 1 and 6.
The compound described in Patent Document 2 is identical to the compound represented by formula (I) described in Patent Document 3, or the compound described in examples. The structural characteristics of this compound are that “it has an indole or indoline skeleton having a cyclic amine that may be substituted by an arylalkyl group or the like as a side chain structure.”
Among the compounds disclosed in Patent Document 3, specific examples of compounds that are close to the compound represented by formula (I) of the present invention may include those represented by the following formula:
wherein R1 and R3 each represent a hydrogen atom; R2 represents a carbamoyl group; R5 represents an arylalkyl group that may be substituted; n and m represent 0; p represents 2; T and Z each represent a nitrogen atom; and Y represents a methine group. The closest compound is the compound described in Example 337. However, these disclosed compounds are limited to compounds, “which have an indole or indoline skeleton having a cyclic amine that may be substituted by an arylalkyl group or the like as a side chain structure.” There are no descriptions suggesting the compound represented by formula (I) of the present invention, “which has an unsubstituted or monosubstituted carbamoyl group at position 6 on an indole skeleton, and has a methoxy group on an aryl group of an aryl alkyl side chain extended from a nitrogen atom on a piperidine ring, at an ortho position to the alkyl side chain.”
Accordingly, the compound described in Patent Document 2 differs from the compound represented by formula (I) of the present invention in terms of chemical structure, and thus, it does not have a chemical structure that is specific to the compound of the present invention.
Moreover, Patent Document 2 describes the test methods of a [3H]-8-hydroxy-dipropylaminotetralin binding test (Test example 1), a 5-HT1A receptor antagonist test (Test example 2), and a test regarding an antagonistic effect against a 5-HT1A receptor agonist-induced hypothermia in a rat (Test example 3). However, the document discloses neither test compounds nor specific test results (pharmacological effects). Thus, it is impossible to grasp the entity of the invention based on such descriptions.
Among the compounds described in Patent Document 3 and Patent Document 2, the compound that is closest to the compound represented by formula (I) of the present invention is the compound described in Example 337, which is represented by the following formula
As described later in the results of pharmacological studies, the pharmacological effect of this compound is characterized in that it has affinity for 5-HT1A but its antagonistic effect against the receptor is weak.
On the other hand, the compound of the present invention represented by the following formula (I):
is characterized in that it has an unsubstituted or monosubstituted carbamoyl group at position 6 on the indole skeleton thereof, and has a methoxy group on an aryl group of an aryl alkyl side chain extended from a nitrogen atom on a piperidine ring, at an ortho position to the alkyl side chain, thereby having an increased antagonism to the 5-HT1A receptor. Therefore, the compound of the present invention has effects that are completely different from those of the compounds described in Patent Document 3 and Patent Document 2.
It is an object of the present invention to provide a compound having affinity for a 5-HT1A receptor and exhibiting an antagonism to the receptor, which is used for therapeutic purposes.
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Patent Document 1: International Publication WO99/06384;
Patent Document 2: JP-A-2002-114684;
Patent Document 3: International Publication WO098/43956.